Transplacental transfer of antigens from mother to fetus often occurs producing a fetal immune response in some cases or fetal immune tolerance in others. In developing countries, transplacental antigen transfer is especially common, since pregnant women are often affected by one or more chronic infections. How transplacental transfer occurs, the nature and variety of the fetal responses generated, and the impact of prenatal exposure on subsequent childhood immunity remain poorly understood. Greater understanding of these fetal immune responses has broad applications in a host of areas, most especially maternal-fetal medicine and neonatal care. Prenatal exposure to exogenous antigens may affect maturation and possible "imprinting" of both innate and adaptive immune responses in early life and such early exposure to infectious agents or antigens can be beneficial or detrimental. In malaria in pregnancy, parasitized erythrocytes (irbc) sequester in the placenta and irbcs or their soluble products cross the placenta during gestation, either priming or tolerizing the fetal immune response. In those newborns who demonstrate immune tolerance, we have shown increased susceptibility to falciparum malaria infection up to 3 years of age. Whether this tolerance affects susceptibility to falciparum or vivax malaria illness throughout childhood is not known. Also unclear is why only some newborns acquire the tolerant phenotype. The immunologic mechanisms mediating this tolerance are poorly understood. Increasing evidence supports the hypothesis that acquired immune tolerance is an active form of immune suppression, rather than a passive functional defect occurring during fetal development and is mediated by regulatory T cells (Tregs). Here we hypothesize that prenatal exposure to malaria antigens induces fetal malaria-specific Tregs that persist into childhood, inhibiting protective immune responses that would normally attenuate severity of illness. We further hypothesize that the timing of fetal exposure to malaria antigens determines whether immune tolerance or fetal priming is acquired. To test these hypotheses we will take advantage of an ongoing project supported by the Malaria in Pregnancy Consortium, where women will be randomized to receive either intensive malaria prophylaxis throughout pregnancy or standard therapy consisting of one-time prophylaxis. Women between 14 and 26 weeks of gestational age will be recruited, resulting in variable timing of prophylaxis (and thus variable timing of malaria exposure) during gestation. PUBLIC HEALTH RELEVANCE: This study will examine the impact of in utero exposure to malaria blood stage antigens on development of fetal immune responses, and whether the fetus is primed or tolerized to these antigens. We will conduct a prospective birth cohort study in an area highly endemic for malaria in Papua New Guinea to determine whether the fetal exposure to malaria and type of immune response acquired affects susceptibility to falciparum or vivax malaria in early childhood.